1. Field of the Disclosure
Degradable comb polymers that individually self-aggregate into unimolecular micelles in an aqueous solution are disclosed. The compositions generally include poly(glycolide) polymers having pendant alkynyl groups that can be functionalized via triazole formation with hydrophilic and other groups. The polymeric micelles can be chemically cross-linked to form organic nanoparticles that retain their chemical functionality and their degradability. The micelles are capable of hydrophobic drug encapsulation and have pendant reactive sites that can be used for cross-linking or covalent drug attachment. The micelles are completely biodegradable and can be used in biomedical applications for controlled drug release.
2. Brief Description of Related Technology
Inorganic nanoparticles have a long and rich history, having benefited from favorable physical properties such as mechanical, thermal, and chemical stability. While comparable developments in organic nanoparticles are more recent, the structural diversity of organic materials and their application to complex problems in medicine has made the synthesis and characterization of organic nanoparticles one of the most active topics in polymer science.1 
Organic nanoparticles are important in many applications, but especially for the encapsulation of small molecules for the delivery of therapeutic agents, personal care products, and colorants.2 Until recently, nearly all applications were based on nanoparticles prepared by spray drying or an oil in water emulsion approach, using homopolymers as the host. The need for “smart” particles in medical applications, to control release rates, target specific sites in the body, and to transport large biomolecules such as single strand RNA for gene therapy, instigated interest in more complicated polymer architectures and function.3-5 A variety of architectural motifs were synthesized including many varieties of linear homopolymers and block copolymers, and branched polymers such as stars, combs, dendrimers, and hyper-branched structures that provide multiple sites (usually at chain ends) for tethering molecules. In contrast to traditional micelles, these structures are “unimolecular”, and correspond to a single molecular entity formed from individual polymer chains and are unaffected by solution concentration.6 
FIGS. 1A and 1B contrast unimolecular micelles (FIG. 1B) to traditional micelles (FIG. 1A) derived from amphiphilic block copolymers. In aqueous solutions, both assemble to form a hydrophilic (blue) exterior 2 and a hydrophobic (red) interior 1 which allows encapsulation of hydrophobic materials. Traditional polymer micelles are derived from low-cost block copolymers, but their aggregation numbers vary and block copolymers often lack functional groups for further elaboration. In addition, the critical micelle concentration (cmc) defines their lower concentration limit for in vivo applications. At low concentrations, as in the blood stream, the equilibrium between the micellar structure and individual surfactant molecules complicates controlled drug release and causes potential toxicity problems.7 These limitations have been overcome by cross-linked micelles to form stable core shell structures,8-17 and introducing chemical functionality to the individual molecules that of the micelle to allow introduction of moieties for cell recognition and imaging. Attaching individual hydrophobic and hydrophilic segments to a polymer backbone creates a brush-like copolymer capable of forming “unimolecular micelles.” Comb polymers seem particularly promising since they can be prepared by controlled polymerization methods and the functional group density can be very high (e.g., about 1 functional group/monomer repeat unit).
There have been several recent examples of cross-linked nanoparticles synthesized by cross-linking well-defined single polymer chains. Using a dilute solution approach Hawker18 and Harth19 cross-linked linear styrene-vinylbenzocyclobutene copolymers and obtained ˜6 nm nanoparticles. Harth extended the o-quinodimethane chemistry19 by—copolymerizing styrene and 5-vinyl-1,3-dihydrobenzo[c]thiophene, extruding SO2 to form the highly reactive o-quinodimethane intermediate and crosslink the polymer.
Thus, there exists a need for an improved drug delivery composition that can serve as a vehicle for delivering a drug in a variety of formats (e.g., encapsulated, covalently attached) in a controlled release manner.